While aging and tobacco are the major risk factors for squamous cell cancer of the oral cavity, alcohol consumption and nutrition also play an important role in the regulation of susceptibility to this disease. The mechanism(s) by which heavy alcohol intake and decreased intake of certain antioxidant/nutrients enhances the risk for oral cancer is unknown but recent studies have suggested than an increase in oxidative stress may be involved. Glutathione (GSH) is the most abundant cellular antioxidant found in all cells and tissues and is thought to play a key role in the regulation of redox status and protection against oxidative stress. Decreased GSH levels occur as a result of heavy alcohol consumption and are also a consequence of the biological aging process. Recent results have implicated a protective role for GSH in oral carcinogenesis. We hypothesis that the GSH content of the oral epithelium is a key regulating factor in the carcinogenic process. Our objectives are to examine the effects of increasing or decreasing GSH levels on oral carcinogenesis in the rat. To this end, we will determine the effects of oral administration of GSH monoethyl ester (GSHME) or butathionine sulfoximine (BSO) on 4-NQO- the effects of oral administration of GSH monoethyl ester (GSHME) or buthionine sulfoximine (BSO) on 4-NQO-induced tongue tumor formation. In addition, we will investigate one possible mechanism by which decreased GSH can lead to increased carcinogenicity, namely, the enhancement of colonic cell proliferation by activation of NF-kappaB and subsequent up-regulation of COX-2 activity. This mechanism will be investigated using specific inhibitors of NF-kappaB and COX-2 in short-term studies in the R-NQO rat model. The relationship between GSH and oral cancer risk in humans will also be examined by correlating blood and tissue GSH levels with dietary intake of GSH and its precursors, and other risk factors for oral cancer including alcohol intake and nutrient/antioxidant levels in healthy subjects. Finally, we will examine if low GSH is a risk factor for precancerous oral lesions using a case-control design. Results from these should provide new and important information on the etiology and regulation of risk of oral cancer in human subjects, and can be used to design effective and systematic preventive strategies for oral cancer. In addition, GSH levels may be useful in the identification of individuals who at high risk for this disease.